Breast cancer is one of the most prevalent types of cancer, and epidemiological and clinical studies have shown that approximately two-thirds of breast tumors are estrogen-dependent. This means that estrogens are required for the growth of such breast tumors in both premenopausal and postmenopausal patients. In postmenopausal women, in whom breast cancer most commonly occurs, breast tumor concentrations of estrone and estradiol are considerably higher than blood estrogen levels. Although retention of estrogens in breast tumors by high-affinity binding proteins contributes to the level of estrogens in tumors, estrogen concentrations in the breast are higher than plasma levels in breast cancer patients regardless of whether their tumors are estrogen receptor-positive (ER+) or estrogen receptor-negative (ER−). In situ formation of estrogen from estrogen biosynthetic precursors within tumors is now known to make a major contribution to the estrogen content of breast tumors.
Numerous other estrogen-dependent conditions, disorders, and diseases have been identified as well, including, but not limited to, ovarian, uterine and pancreatic cancers, galactorrhea, McCune-Albright syndrome, benign breast disease, and endometriosis.
Estrogenic effects are mediated by specific receptors located in the nucleus of estrogen-responsive cells. The receptor contains a hormone-binding domain for binding estrogen, transcription activating domains, and a DNA binding domain. The binding of the receptor-hormone complex to estrogen response elements (ERE's) in the DNA of target genes is necessary for regulating gene transcription.
Drugs that competitively block estrogen binding to its receptor, termed anti-estrogens, are capable of inhibiting the stimulatory effects of the hormone on cell proliferation and are therefore useful in the clinical treatment of breast cancer. Clinically, estrogen receptor-positive tumors respond with a higher frequency to anti-estrogens than do tumors lacking a significant level of receptors.
Anti-estrogenic drugs fall into two chemical classes: nonsteroidal and steroidal. The nonsteroidal anti-estrogen tamoxifen (Nolvadex) has been used as an adjunctive treatment for breast cancer following chemotherapy or radiation therapy. However, tamoxifen itself exhibits estrogenic activity in reproductive tissue, resulting in an increased risk of endometrial cancer and possible recurrence of breast cancer after long-term therapy. Furthermore, tamoxifen behaves only as a partial agonist in the uterus.
To date, little work has been done in the development of selective competitive antagonists of estrogen. Several steroidal anti-estrogens have been synthesized which lack estrogenic activity. Included among these are ICI 164,384, ICI 182,780 and RU 58668. See, e.g.: Wakeling et al. J. Steroid Biochem. 31:645-653 (1988), which pertains to ICI 164,384; Wakeling et al., Cancer Res. 51:3867-3873 (1991), and Wakeling et al., J. Steroid Biochem. Molec. Biol. 37:771-774 (1990), which pertain to ICI 182,780; and Van de Velde et al., Ann. N.Y. Acad. Sci. 761:164-175 (1995), Van de Velde et al., Pathol. Biol. 42:30 (1994), and Nique et al., Drugs Future 20:362-366 (1995), which relate to RU 58668. Unfortunately, these drugs are not orally active and must be administered in high doses intramuscularly. Furthermore, the manufacture of these drugs is laborious, requiring a complicated, 14-16 step synthesis with very low overall yields. Potent steroidal anti-estrogens that are orally active have not yet been developed or commercialized, although the nonsteroidal mixed agonist/antagonist “raloxifene” is currently available.
Accordingly, steroidal active agents have recently been developed that are extremely effective anti-estrogenic agents, i.e., are potent antagonists of estrogen in breast and/or uterine tissue. The active agents are described in co-pending, commonly assigned U.S. patent application Ser. No. 08/998,877, filed Dec. 24, 1997, now U.S. Pat. No. 6,054,446, and U.S patent application Ser. No. 09/220,408, filed Dec. 23, 1998, (now U.S. Pat. No. 6,281,205) as well as in PCT Publication No. WO 99/33859, published Jul. 8, 1999. These active agents represent a significant advance in the art, particularly in the treatment of breast cancer and other diseases and conditions that are potentiated by the presence of estrogens. A number of those active agents have also been found to display tissue-selective pharmacology and are thus useful as tissue-selective estrogen agonists/antagonists, also termed “Selective Estrogen Receptor Modulators” or “SERMs.” SERMs produce beneficial estrogen-like effects in some respects, notably on bone and lipid metabolism, while nevertheless acting as estrogen antagonists in the breast and/or uterus. The SERM profile may be distinguished from that of a pure estrogen such as 17β-estradiol, which behaves as an estrogen agonist in all tissues, and from that of a pure anti-estrogen, which exhibits an estrogen antagonist profile in all tissue types.
An exemplary and representative anti-estrogen in the aforementioned group is the citrate salt of 3-hydroxy-7α-methyl-21-[2′-methoxy-4′-(diethylaminomethyl)-phenoxy]-19-norpregna-1,3,5(10)triene, developed at SRI International (Menlo Park, Calif.) and also referred to herein as “SR 16234.” SR 16234 can be represented as follows:
SR 16234 has been found to have potent antitumor activity with remarkable tissue-selective properties: complete antagonist-antiestrogenic activity in human breast tumor cells; complete anti-uterotrophic antagonist activity in rat and human uterine tissue; agonist-estrogenic activity in the cardiovascular system, as reflected in lowered low-density lipoprotein (LDL) and increased high-density lipoprotein (HDL) cholesterol levels in rats; and agonist-estrogenic activity in the skeletal system, as manifested by maintenance of bone and prevention of bone loss in rats. In addition, SR 16234 has been established to have good oral bioavailability, absorption and half-life, with sufficient uptake to sustain therapeutically effective plasma levels of the drug.
Currently, SR 16234 is synthesized using a nine-step synthetic procedure as outlined in FIG. 1. While the synthesis is effective and provides the product in a reasonable overall yield, it would be desirable to provide a simpler, more straightforward synthesis so as to reduce cost (synthesizing SR 16234 using the method of FIG. 1 is quite expensive), to improve overall yield, to avoid use of highly toxic reagents, and to avoid costly and difficult reaction steps such as aromatization with CuCl2.